ArticleProceedings of the National Academy of Sciences of the United States of America2011
Engineering hepatocyte growth factor fragments with high stability and activity as Met receptor agonists and antagonists.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2011. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 29 papers.
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Who cites it
29 citing papers in PubMed, 55 citations in OpenAlex.
- Hydrogels loaded with different substances for treating heart failure: a promising therapy.Frontiers in cardiovascular medicine · 2026Review
- Engineering Affibody Binders to Death Receptor 5 and Tumor Necrosis Factor Receptor 1 With Improved Stability.Biotechnology and bioengineering · 2025Article
- New treatment methods for myocardial infarction.Frontiers in cardiovascular medicine · 2023Review
- HGF and MET: From Brain Development to Neurological Disorders.Frontiers in cell and developmental biology · 2021Review
- Engineering, Characterization, and Biological Evaluation of an Antibody Targeting the HGF Receptor.Frontiers in immunology · 2021Article
- Cyclic Peptide-Based Biologics Regulating HGF-MET.International journal of molecular sciences · 2020Review
- Increasing thermal stability and improving biodistribution of VEGFR2-binding affibody molecules by a combination of in silico and directed evolution approaches.Scientific reports · 2020Article
- Nanoscale integration of single cell biologics discovery processes using optofluidic manipulation and monitoring.Biotechnology and bioengineering · 2019Review
- Engineering a potent inhibitor of matriptase from the natural hepatocyte growth factor activator inhibitor type-1 (HAI-1) protein.The Journal of biological chemistry · 2018Article
- Development of a Protease Biosensor Based on a Dimerization-Dependent Red Fluorescent Protein.ACS chemical biology · 2018Article
- A novel protein-engineered hepatocyte growth factor analog released via a shear-thinning injectable hydrogel enhances post-infarction ventricular function.Biotechnology and bioengineering · 2017Article
- Utilizing combinatorial engineering to develop Tie2 targeting antagonistic angiopoetin-2 ligands as candidates for anti-angiogenesis therapy.Oncotarget · 2017Article
- Dual display of proteins on the yeast cell surface simplifies quantification of binding interactions and enzymatic bioconjugation reactions.Biotechnology journal · 2017Article
- Hepatocyte growth factor and alternative splice variants - expression, regulation and implications in osteogenesis and bone health and repair.Expert opinion on therapeutic targets · 2016Review
- Degradable acetalated dextran microparticles for tunable release of an engineered hepatocyte growth factor fragment.ACS biomaterials science & engineering · 2016Article
- Engineering growth factors for regenerative medicine applications.Acta biomaterialia · 2016Review
- Antifibrotic therapies to control cardiac fibrosis.Biomaterials research · 2016Review
- Cell-Binding Assays for Determining the Affinity of Protein-Protein Interactions: Technologies and Considerations.Methods in enzymology · 2016Article
- Semi-synthesis of a HGF/SF kringle one (K1) domain scaffold generates a potentChemical science · 2015Article
- Delivery of an engineered HGF fragment in an extracellular matrix-derived hydrogel prevents negative LV remodeling post-myocardial infarction.Biomaterials · 2015Article
Corrections and comments
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Authors and funding
3 authors at 1 institution in 1 country.
Funding
Abstract
The Met receptor tyrosine kinase and its ligand hepatocyte growth factor (HGF) play an important role in mediating both tumor progression and tissue regeneration. The N-terminal and first Kringle domains (NK1) of HGF comprise a naturally occurring splice variant that retains the ability to activate the Met receptor. However, NK1 is a weak agonist and is relatively unstable, limiting its therapeutic potential. Here, we engineered NK1 mutants with improved biochemical and biophysical properties that function as Met receptor agonists or antagonists. We first engineered NK1 for increased stability and recombinant expression yield using directed evolution. The NK1 variants isolated from our library screens acted as weak Met receptor antagonists due to a mutation at the NK1 homodimerization interface. We introduced point mutations that restored this NK1 homodimerization interface to create an agonistic ligand, or that further disrupted this interface to create more effective antagonists. The rationally engineered antagonists exhibited melting temperatures up to approximately 64 °C, a 15 °C improvement over antagonists derived from wild-type NK1, and approximately 40-fold improvement in expression yield. Next, we created disulfide-linked NK1 homodimers through introduction of an N-terminal cysteine residue. These covalent dimers exhibited nearly an order of magnitude improved agonistic activity compared to wild-type NK1, approaching the activity of full-length HGF. Moreover, covalent NK1 dimers formed from agonistic or antagonistic monomeric subunits elicited similar activity, further signifying that NK1 dimerization mediates agonistic activity. These engineered NK1 proteins are promising candidates for therapeutic development and will be useful tools for further exploring determinants of Met receptor activation.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.